135. Passive infusion of potently-neutralizing hyperimmune globulin can protect against cytomegalovirus congenital infection in a rhesus monkey model
Session: Poster Abstract Session: Big Viruses in Little People (Pediatric Viral Diseases)
Thursday, October 27, 2016
Room: Poster Hall
Posters
  • CSN IDWeek Poster 20161024.pdf (1.9 MB)
  • Background: Cytomegalovirus (CMV) is the most common congenital infection worldwide, and a significant cause of infant hearing loss, brain damage, and neurodevelopmental delay. One potential therapeutic intervention to eliminate this disease is a maternal vaccine that blocks placental CMV transmission. Previously, we demonstrated a role for maternal CMV-neutralizing antibodies in protection against congenital CMV using a rhesus monkey model. In our model, CD4+ T cell depleted dams with delayed neutralizing antibody responses experienced high rates of placental transmission (100%) and fetal loss (75%) shortly after rhesus CMV (rhCMV) challenge.

    Methods: To further investigate the protection conferred by maternal CMV-neutralizing antibodies, 6 rhCMV-seronegative rhesus macaque dams in the second trimester of pregnancy were CD4+ depleted. One week later, 3 dams were administered a single dose (100mg/kg) of hyperimmune globulin (HIG) with a low neutralizing potency (IC50=22.64µg/mL) 1 hour prior to intravenous (IV) challenge with a mixture of fibroblast-adapted (180.92) and epithelial-tropic (UCD52/UCD59) rhCMV strains. The remaining 3 dams received 2 doses (125+100mg/kg) of a potently-neutralizing HIG product (IC50=5.88µg/mL) at 1 hour prior to IV rhCMV inoculation and 3 days post-infection, respectively.

    Results: Passive infusion of HIG prior to IV rhCMV challenge of CD4+ depleted dams provided complete protection against fetal loss (0/6 dams aborted; p<0.01). Furthermore, 2 doses of the highly-neutralizing HIG product achieved protection from placental transmission of rhCMV (0/3 transmitted), while a single dose of low-potency HIG product did not (2/3 dams transmitted). Peak plasma viral load was decreased in all HIG treated animals. Furthermore, targeted deep sequencing of rhCMV glycoprotein L (gL) and glycoprotein B (gB) from maternal plasma revealed that infused HIG created a genetic bottleneck, decreasing the diversity of viral haplotypes at both loci.

    Conclusion: Our data suggest that the presence of highly-neutralizing antibodies at the time of rhCMV acquisition can prevent congenital infection, perhaps by influencing early viral replication. A better understanding of how antibody-mediated selection impacts placental rhCMV transmission and fetal outcome will inform future vaccine development efforts.

    Cody Nelson, BS1, Kristy Bialas, PhD1, Dollnovan Tran, BS2, Amitinder Kaur, MD2 and Sallie Permar, MD/PhD1, (1)Duke Human Vaccine Institute, Duke University, Durham, NC, (2)Tulane National Primate Research Center, Tulane University, Covington, LA

    Disclosures:

    C. Nelson, None

    K. Bialas, None

    D. Tran, None

    A. Kaur, None

    S. Permar, None

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